Role of transfusion-transmitted virus in acute viral hepatitis and fulminant hepatic failure of unknown etiology

BACKGROUND AND AIM: The role of the newly described transfusion-transmitted virus (TTV), a circular single-stranded DNA virus, has been investigated in acute liver disease, comprising 36 patients with acute viral hepatitis (AVH) and 25 with fulminant hepatic failure (FHF), including 50 volunteer blood donors as controls. METHODS: Detection of TTV DNA sequences was carried out by polymerase chain reaction (PCR) using primers derived from the UTR(A) region of the TTV genome. The clinical course and biochemical profile when infected with TTV alone or coinfected with other classical hepatotropic viruses were analyzed. All patients were first evaluated for liver function profile and for the presence of various hepatotropic viruses using serological tests and PCR in serologically negative patients. RESULTS: Transfusion-transmitted virus DNA was detected in 80.6% (29/36) of the AVH cases and in 76% (19/25) of the FHF cases, which were significantly higher levels (P < 0.05) than the 52% (26/50) observed in volunteer blood donors. No significant difference in symptoms, clinical course, liver function and risk factor profile between TTV-positive and TTV-negative patients could be observed in both AVH and FHF patients. TTV was found to coexist with both parenterally and non-parenterally transmitted hepatotropic viruses in similar frequency in both AVH and FHF patients. Further, there was no significant difference in the mortality rates between TTV-positive and TTV-negative FHF patients. Also, there was no difference between patients coinfected by TTV and other hepatotropic viruses and those with TTV infection alone. CONCLUSION: Thus, it appears that TTV, although it exists in a very high frequency in the Indian population, appears to have no significant etiological role in AVH and FHF.     

Aplastic Anemia Frequency and Management in Pediatric Liver Transplantations Due to Non-A-E Hepatitis

Background: Hepatitis-associated aplastic anemia (HAAA) is a rare complication that presented with bone marrow failure after acute hepatitis. HAAA usually occurs in adolescent men within 1-6 months following hepatitis. Most of HAAA’s etiology has non-A-E viral hepatitis.Methods: Our retrospective study included patients with acute fulminant hepatitis who had been treated in Ege University Pediatric Gastroenterology, Hepatology and Nutrition Department and İzmir Kent Hospital Clinical, laboratory, and epidemiological data of the patients were collected from the files.Results: In this study, 499 children underwent liver transplantation (LT) in two pediatric transplantation centers. Sixty-eight (13.6%) out of 499 patients, underwent liver transplantation due to fulminant hepatic failure (FHF). Therefore, a total of 64 patients (34 girls, 30 boys) with a diagnosis of FHF have included in the study. Thirty-two (50.0%) of 64 FHF were due to non-A-E hepatitis and 4 out of the 64 patients (6.2%) with FHF developed HAAA. All of the patients received prednisolone as immunosuppression treatment after LT. Three patients were also given Tacrolimus and 1 received an additional mycophenolate mofetil. One of the patients was given prednisolone and cyclosporine treatment without tacrolimus. Bone marrow transplantation was performed in 1 patient (25.0%). Two of the patients received immunosuppressive treatment including rabbit-derived anti-thymocyte globulin, cyclosporine, and initially prednisolone.Conclusion: In children who underwent liver transplantation for non-A-E FHF are at high risk to develop aplastic anemia. The clinicians should be alert after orthotropic liver transplantation patient could develop aplastic anemia and early treatment with immunosuppressive therapies result in a more successful outcome.     

Importance of measuring plasma thrombin-antithrombin III complex levels when using antithrombin III concentrate therapy in fulminant hepatic failure.

We investigated changes in the concentrations of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC) after the intravenous administration of 4000 units of antithrombin III (AT III) concentrate to patients with fulminant hepatic failure (FHF), subacute hepatitis (SH), or liver cirrhosis (LC). FHF patients showed shortening of the initial half-life of exogenous AT III. In addition, a marked rise in plasma TAT was noted 3 to 6 h after the intravenous administration of AT III, even in patients who had a normal plasma TAT level before AT III therapy. In contrast, SH and LC patients showed no marked changes of plasma TAT levels after AT III administration. No marked changes were observed in the PIC concentration in any of the patients. These findings suggest that thrombin formation is increased in FHF and that simple measurement of the plasma TAT concentration is not an adequate method for assessing thrombin formation in FHF patients who have suspected disseminated intravascular coagulation associated with an apparent decrease in AT III synthesis. Instead, it seems necessary to measure the plasma TAT concentration in FHF patients after replacement therapy with AT III concentrate has been performed, to evaluate their hypercoagulability more accurately.     

Induction of Autoimmune Colitis by Yersinia enterocolitica 60-kilodalton Heat-Shock Protein

We investigated changes in the concentrations of thrombin-antithrombin III complex (TAT) and plasmin-α₂ plasmin inhibitor complex (PIC) after the intravenous administration of 4000 units of antithrombin III (AT III) concentrate to patients with fulminant hepatic failure (FHF), subacute hepatitis (SH), or liver cirrhosis (LC). FHF patients showed shortening of the initial half-life of exogenous AT III. In addition, a marked rise in plasma TAT was noted 3 to 6h after the intravenous administration of AT III, even in patients who had a normal plasma TAT level before AT III therapy. In contrast, SH and LC patients showed no marked changes of plasma TAT levels after AT III administration. No marked changes were observed in the PIC concentration in any of the patients. These findings suggest that thrombin formation is increased in FHF and that simple measurement of the plasma TAT concentration is not an adequate method for assessing thrombin formation in FHF patients who have suspected disseminated intravascular coagulation associated with an apparent decrease in AT III synthesis. Instead, it seems necessary to measure the plasma TAT concentration in FHF patients after replacement therapy with AT III concentrate has been performed, to evaluate their hypercoagulability more accurately.     

Living donor liver transplantation for fulminant hepatic failure

Aim: The aim of this study was to investigate the safety of living donor liver transplantation (LDLT) for fulminant hepatic failure (FHF) patients. Methods: We reviewed the clinical indications, operative procedures and prognosis of LDLT performed on patients with FHF at the University of Tokyo. From January 1996 to August 2007, 96 patients were referred to our department due to severe acute hepatitis or FHF. Of these, 36 underwent LDLT and were the subjects of this study. Of the 36 patients who underwent LDLT, 32 were over 18 years old. The etiologies of FHF included non‐A, non‐B hepatitis in 23, hepatitis B virus in 11, Wilson's disease in one, and auto‐immune hepatitis in one. Graft type included right liver in 18, left liver in 16 and right paramedian sector in two. Results: Patient and graft survival rates at 5 years were 87% and 82%, respectively. Twenty‐three patients had postoperative complications: acute cellular rejection in 12, biliary stricture in eight, bile leakage in six, peritoneal hemorrhage in six and hepatic arterial thrombosis in four. Conclusion: The LDLT procedure provided satisfactory survival rates for FHF patients.     

Fulminant non--A-G viral hepatitis leading to liver transplantation

BACKGROUND: All hepatotropic viruses are known to cause fulminant hepatic failure (FHF). However, in 30% to 40% of patients with FHF, the precise cause remains unknown. We aimed to better define this subgroup. METHODS: We evaluated the clinical course and outcome of 7 patients admitted during a 22-month period with fulminant viral hepatitis leading to liver transplantation; none had serologic or molecular evidence of hepatitis A, B, C, D, E, or G viral infection, thus the term non-A-G viral hepatitis. All known etiologies of FHF were excluded. RESULTS: All patients had prodromal symptoms suggestive of viral causes. Mean age was 30 years. The interval between onset of jaundice and appearance of encephalopathy was 23 days (range, 4-50 days). Five patients had grade III/IV encephalopathy. Serum alanine aminotransferase levels showed a single peak of activity. The duration between first symptoms and liver transplantation was 28 days (range, 12-71 days). Results of histological study of the explanted liver showed submassive (4 patients) or massive (3 patients) hepatocyte necrosis. In all patients, results of polymerase chain reaction analysis did not detect hepatitis B virus DNA, hepatitis C virus RNA, or hepatitis G virus RNA in the explanted liver. After transplantation, 2 patients showed (6 months later) increased liver enzyme levels of undetermined cause, and results of a liver biopsy showed mild lobular hepatitis; 1 patient had lymphoproliferative disorder (Epstein-Barr virus-originated); and 1 patient, aplastic anemia, which is known to be associated with seronegative viral hepatitis. The latter patient died, whereas the other 6 patients are alive (survival rate, 86%). CONCLUSIONS: Our patients with non-A-G viral hepatitis had a severe acute onset with progressive FHF requiring liver transplantation. There is some suggestion of recurrent viral disease after transplantation implicating other unknown viruses in the etiology.     

Value of computed tomography-derived estimated liver volume/standard liver volume ratio for predicting the prognosis of adult fulminant hepatic failure in Japan

BACKGROUND AND AIMS: The prognosis of fulminant hepatic failure (FHF) has been improved but is still unsatisfactory, and liver atrophy has been reported as a poor prognostic factor for this disease. The aim of this study was to assess the clinical value of the estimated liver volume (ELV) compared to the standard liver volume (SLV) in patients with FHF. METHODS: Estimated liver volume of 24 adult patients with FHF receiving artificial liver support (ALS) was measured by using computed tomography. Actual liver weight (ALW) was measured if possible, and the calculated ELV/SLV ratio was compared to the ALW/SLV ratio and the ALW/BW (bodyweight) ratio. Sequential ELV/SLV ratios during the clinical course were analyzed in relation to the prognosis. RESULTS: The ELV/SLV ratio was significantly correlated with both the ALW/SLV and ALW/BW ratios. The mean ALW/SLV ratio of patients who underwent living donor liver transplantation (LDLT) was 0.59 +/- 0.17. The mean ELV/SLV ratio at the time of starting ALS (day 0) in the patients who survived (group 1) was 1.081 +/- 0.183, but that of cases who underwent LDLT or died without LDLT (group 2) was 0.764 +/- 0.255. The mean ELV/SLV ratios were 1.084 +/- 0.222 and 0.650 +/- 0.195 in groups 1 and 2, respectively, 5 days after starting ALS (day 5). Among the group 2 patients, those who had no liver atrophy on day 0 had a significantly decreased ELV/SLV ratio on day 5. CONCLUSIONS: These results suggest that the ELV/SLV ratio is a very useful objective marker to estimate liver atrophy and this marker reflects the prognosis of FHF patients very well.     

Fulminant hepatic failure: Summary of a workshop

Fulminant hepatic failure (FHF) is defined by the appearance of severe liver injury with hepatic encephalopathy in a previously healthy person. There are an estimated 2,000 cases of FHF in the United States yearly, representing 0.1% of all deaths and, perhaps, 6% of liver-related deaths. The causes of FHF are many, the chief ones in the United States being hepatitis A; B; non-A, non-B and drug induced liver disease. There are no specific therapies for FHF, however, liver transplantation is recommended for situations in which spontaneous recovery appears unlikely. Factors that are valuable in assessing the likelihood of spontaneous recovery are static features such as patient age and etiology of FHF and dynamic features including encephalopathy grade, prothrombin time, and serum bilirubin. Presently, approximately 7% of all liver transplants are done for FHF and the 1-year patient survival rates average 63%, somewhat less than survival rates for nonfulminant liver disease, averaging 78%. The management of patients with FHF is challenging, particularly important being monitoring and early treatment of infections, hemodynamic abnormalities, and brain edema. Innovative approaches to management and therapy include use of cytoprotective or antiviral medications, hepatic support systems, extracorporeal liver support, hepatocyte transplantation, auxiliary liver transplantation, and xenotransplantation. None of these are of proven benefit, but many are promising as a means to support the patient with FHF until spontaneous recovery occurs or a suitable liver graft is available for transplantation.     

Non-A, Non-B Fulminant Hepatitis is also Non-E and Non-C

Objectives : to define the roles of the hepatitis C and E viruses (HCV and HEV) in non-A, non-B (NANB) fulminant hepatitis. Methods : we utilized the polymer-ase chain reaction to amplify HCV and HEV RNA sequences and assays to detect antibodies to HCV and HEV in the acute phase sera of eight presumed viral NANB and seven nonviral NANB fulminant hepatic failure (FHF) patients. Results : none of the 15 patients had detectable HCV or HEV RNA or elevated HCV and IgM-HEV antibody titers in their acute phase sera. Three patients, all with features of autoimmune hepatitis, had raised IgG-HEV antibody titers. Due to the possibility of serologically undetectable hepatitis B virus (HBV) infection in fulminant hepatitis patients, we performed polymerase chain reaction amplification of HBV genomic DNA in acute phase sera of the presumed viral NANB FHF patients and subsequently found no evidence of HBV DNA. Conclusions: we did not find evidence implicating HCV or HEV in presumed viral NANB FHF or as agents contributing to or causing the liver failure in nonviral NANB FHF patients with au-toimmune hepatitis, drug-induced hepatotoxicity, or ha-lothane hepatotoxicity.     

Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination

To investigate the role of hepatitis B virus (HBV) infection in pediatric fulminant hepatic failure (FHF) after the launch of universal HBV vaccination, the authors analyzed the data from patients with FHF collected from a nationwide collaborative study group. Children aged 1 month to 15 years who were diagnosed with FHF (62 males and 33 females) between 1985-1999 were included. HBV infection (hepatitis B surface antigen [HBsAg] and/or immunoglobulin M hepatitis B core antibody [IgM anti-HBc] seropositive) accounted for 46% (43 of 95 cases) of all the cases of FHF. The average annual incidence of FHF in the time period 1985-1999 was 0.053/100,000 in the group of patients ages 1-15 years and 1.29/100,000 in those patients age < 1 year. Approximately 61% (58 of 95 cases) of all FHF cases were infants. The percentage of HBV infection was found to be higher in infants (57%) compared with children ages 1-15 years (27%) (P = 0.004). The incidence rate ratio of those patients age < 1 year to those ages 1-15 years was 54.2 for HBV-positive FHF and 15.2 for HBV-negative FHF. Maternal HBsAg was found to be positive in 97% of the infants with HBV-positive FHF, and hepatitis B e antigen (HBeAg) was found to be negative in 84% of these infants. Approximately 74% of all HBV-positive FHF patients and 81% of the infantile HBV-positive patients had been vaccinated. In conclusion, within the first 15 years of universal vaccination, HBV was found to rarely cause FHF in children age > 1 year but remained a significant cause of FHF in infants. HBV-positive FHF was prone to develop in infants born to HBeAg-negative, HBsAg-carrier mothers; these infants had not received hepatitis B immunoglobulin according to the vaccination program in place.     

Auxiliary liver transplantation: Regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure–a multicenter European study

Auxiliary liver transplantation (LT) is a special procedure of LT which could be proposed to patients with fulminant hepatic failure (FHF) and has for aim that complete regeneration of the native liver (NL) left in place will allow the graft recipient to resume normal liver function after allograft withdrawal. We report 30 cases of auxiliary LT performed for FHF in 12 European centers. Twenty-five of 30 patients were younger than 50 years. The cause of FHF was hepatitis A virus (HAV) in 4 patients, hepatitis B virus (HBV) in 7, paracetamol overdose in 5, ecstasy in 2, hepatotoxic drugs in 4, autoimmune hepatitis in 2, liver lesions of preeclampsia in 1 and unknown in 5. A postoperative, both clinical and histological follow-up of more than 3 weeks was obtained in 22 patients, enabling us to look for indicators predictive of NL regeneration and outcome. Histological changes observed in the NL included complete regeneration in 68%, incomplete regeneration with obvious fibrous sequelae in 14% and severe liver fibrosis or cirrhosis in 18%, of the 22 patients studied. The percentage and distribution of necrosis observed in tissue samples of the NL at the time of transplantation was not related to the final outcome. Complete NL regeneration was observed in 15 patients, out of whom 14 were younger than 40 years. Patients with complete regeneration were mainly affected by FHF due to HAV, HBV, or paracetamol overdose. After a follow-up of 18/11 (mean/median) months (range, 3 to 67 months), 19 of the 30 patients (63%) survived and 13 of them (68%), i.e., 43% of the 30 patients, had resumed normal NL function, with interrupted immunosuppression, the ultimate goal of emergency auxiliary LT. We conclude that, in patients with FHF, auxiliary LT is a procedure feasible in a number of centers and is associated with a complete regeneration capability of the NL in a majority of survivors, especially in those younger than 40 years. Confirmation of these encouraging preliminary results by large-scale prospective studies is required. (Hepatology 1996 May;23(5):1119-27)     

Serum osteopontin levels in patients with acute liver dysfunction

OBJECTIVE: Fulminant hepatic failure (FHF) is a clinical syndrome of sudden and severe liver dysfunction accompanied by encephalopathy in a previously healthy person. In FHF, hepatocytes are severely damaged and ordinary liver regeneration is impaired. We demonstrated that the expression of osteopontin (OPN), a multifunctional cytokine, was up-regulated in mouse oval cell (a stem-cell progenitor) induction models. MATERIAL AND METHODS: Based on this finding, serum OPN levels were examined in 43 patients with FHF and in 45 patients with acute self-limited hepatitis (AH). To determine the cellular source of OPN, the expression of OPN was studied in a liver specimen derived from an FHF patient. RESULTS: The mean OPN level of patients with FHF was 2.80+/-0.48 ng/ml (log(10), +/-SD), which was significantly higher than that of the patients with AH (2.42+/-0.39 ng/ml) (p=0.003, unpaired t-test). Patients with elevated serum OPN levels had a significantly poorer prognosis than patients whose serum OPN levels were not elevated. In the FHF patient's liver, OPN protein was expressed not only in inflammatory cells but also in regenerating hepatocytes and bile ductular structures. CONCLUSIONS: Our current study indicates that serum OPN levels increased in patients with FHF and that OPN might play an important role in liver regeneration due to activation of hepatic stem cells.     

Etiology and outcome of fulminant hepatic failure managed at an Australian liver transplant unit

BACKGROUND AND AIMS: The primary aims were to identify the incidence, etiology and outcome of all adult cases of fulminant hepatic failure (FHF) presenting to the Victorian Liver Transplant Unit over the 14 year period since the Unit was established in 1988. METHODS: The database of the Unit was used to identify all adult patients (>16 years) who were referred to the Austin and Repatriation Medical Center in Melbourne with FHF between 1988 and 2001. The Austin and Repatriation Medical Center is the sole provider of adult liver transplantation services for the states of Victoria and Tasmania. RESULTS: 80 patients (64 female, 14 male) with FHF were referred, at a rate of approximately one case per million population per year. The mean age was 37.6 +/- 13.7 years. Most cases were due to either paracetamol poisoning n = 29 (36%) or non-A non-B (idiopathic) hepatitis n = 27 (34%). Thirty-five patients were listed for transplantation, of which 26 underwent the procedure (77% of transplantation patients currently alive). Nine patients were listed for transplantation but did not undergo the procedure, eight died before a donor became available and one recovered. Of the 30 patients who survived without transplantation, 20 cases were due to paracetamol poisoning. CONCLUSIONS: Liver transplantation has had a major impact on survival of patients with FHF, most significantly in patients with FHF due to causes other than paracetamol poisoning, in whom survival without transplantation is uncommon. Survival in those who undergo transplantation for FHF is excellent, but a significant percentage of patients listed for transplantation die before a donor organ becomes available.     

Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure

Data reported by Bernuau et al. have strongly supported the measurement of coagulation factor V as the best prognostic indicator in fulminant hepatic failure (FHF) and as the test on which selection for urgent liver transplantation should be made. In this study, we have measured plasma factor V in 110 patients with FHF, in grades I-IV coma, in 88 of whom the etiology was acetaminophen overdose. On admission, patients who did not survive had significantly lower factor V levels (median, 5%; range, 1-27; n = 49), compared with those who did (median, 10%; range, 2-70; P < .001). In the 81 patients with acetaminophen-induced FHF who did not receive a transplant, there was no cutoff level of factor V that clearly separated the patients. On statistical analysis, a positive predictive value (the mortality in patients predicted to have a poor prognosis) of 0.49 was calculated for factor V <20% and 0.57 for factor V < 10%. If the prognostic criteria included deep coma (grades III and IV) as well as factor V <20%, a positive predictive value of 0.73 was calculated. This compared with a value of 0.92 for the well-established King's prognostic criteria based on pH, and a combination of international normalized ratio (INR), renal failure, and coma. In the 17 mixed, nonacetaminophen group of patients who did not receive a liver graft, the positive predictive value was 0.85 for a factor V level <20% and 1.00 for factor V <10%, compared with 0.93 for the King's criteria for that etiologic group. This study demonstrates that the predictive accuracy of plasma factor V level is much less effective than the well-validated King's criteria in the selection of patients with acetaminophen-induced FHF needing liver grafting, although it may be useful in patients with FHF due to other causes. (Hepatology 1996 Jun;23(6):1507-11)     

重型乙型肝炎患者肝组织中人纤维介素基因的检测及其与临床转归关系的探讨

目的 研究人纤维介素基因或纤维介素／hfg12凝血酶原酶(简称hfg12)在重型肝炎、慢性肝炎、肝硬化患者肝组织及非配对患者外周血单个核细胞(PBMC)中的表达，分析其表达与患者临床表现和肝功能的关系，探讨hfg12检测对预测患者临床转归和预后的价值。方法 采用免疫组织化学法和免疫细胞化学法分别检测23例重型肝炎、13例慢性肝炎、14例肝硬化患者的肝组织和30例重型肝炎、10例慢性肝炎患者、10例健康对照者PBMC中的hfg12表达。应用多媒体彩色图文分析系统对hfg12的表达进行半定量分析。结果 23例重型肝炎患者肝组织中，21例可见hfg12表达，而在慢性乙型肝炎、乙型肝炎肝硬化患者肝组织中均无hfg12表达。肝组织中hfg12表达水平与血清总胆红素值呈正相关。30例重型肝炎患者中，28例外周血白细胞hfg12高表达，10例慢性乙型肝炎患者中有1例PBMC可检测到hfg12，健康对照组未检测到hfg12。PBMC中hfg12表达水平与血清总胆红素值呈正相关。结论 Hfg12的表达为重型肝炎所特有的现象，hfg12的表达与乙型肝炎患者病情的严重程度密切相关。减少和阻断其表达有可能为防治重型肝炎提供新的途径和方法。PBMC中hfg12的检测可能有助于重型肝炎的早期诊断和临床转归的判断。     

Hepatitis δ virus infection in India

Serological markers of hepatitis δ virus (HDV) and hepatitis B virus (HBV) infection were studied in 87 HBsAg positive patients, comprised of 18 patients with uncomplicated acute viral hepatitis (AVH), 34 patients with fulminant hepatic failure (FHF), 18 patients with subacute hepatic failure (SAHF) and 17 patients with chronic active hepatitis (CAH). The prevalence of HDV infection was found to be 27.8%, 20.6%, 16.7% and 11.8%, respectively in these four groups. Co-infection of HDV and HBV was common amongst patients with AVH but superinfection by HDV in chronic HBV carriers was the predominant form of infection in patients with FHF, SAHF and CAH. HDV superinfection in these groups did not significantly alter the common tests of liver function or the DNA-polymerase positivity.     

Fulminant hepatic failure secondary to neoplastic infiltration of the liver

Two patients with previously normal liver function, who presented with fulminant hepatic failure (FHF) of unknown etiology despite an extensive evaluation, are described. No etiology for FHF was apparent with initial evaluation. One patient was found to have nearly complete replacement of hepatic parenchyma by metastasis from an occult small cell lung carcinoma identified postmortem. The other patient had lymphomatous infiltration of the liver detected by a liver biopsy. Imaging studies were performed in the patients and did not reveal any evidence of neoplastic infiltration of the liver. Neoplastic involvement of liver should be considered in the differential diagnosis of FHF of unknown etiology. The imaging studies in this setting can be misleading.